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Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion.

Yamamoto T, Byun J, Zhai P, Ikeda Y, Oka S, Sadoshima J - PLoS ONE (2014)

Bottom Line: The protective effect of NMN was accompanied by decreases in acetylation of FoxO1, but it was not obvious in Sirt1 KO mice, suggesting that the effect of NMN is mediated through activation of Sirt1.The protective effect of CR against I/R injury was not significant in cardiac-specific Sirt1 KO mice, suggesting that the protective effect of CR is in part mediated through the Nampt-Sirt1 pathway.In conclusion, exogenous application of NMN and CR protects the heart by both mimicking IPC and activating Sirt1.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, New Jersey, United States of America.

ABSTRACT
Nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme for nicotinamide adenine dinucleotide (NAD+) synthesis, and Sirt1, an NAD+-dependent histone deacetylase, protect the heart against ischemia/reperfusion (I/R). It remains unknown whether Nampt mediates the protective effect of ischemic preconditioning (IPC), whether nicotinamide mononucleotide (NMN, 500 mg/kg), a product of Nampt in the NAD+ salvage pathway, mimics the effect of IPC, or whether caloric restriction (CR) upregulates Nampt and protects the heart through a Sirt1-dependent mechanism. IPC upregulated Nampt protein, and the protective effect of IPC against ischemia (30 minutes) and reperfusion (24 hours) was attenuated at both early and late phases in Nampt +/- mice, suggesting that Nampt plays an essential role in mediating the protective effect of IPC. In order to mimic the effect of Nampt, NMN was administered by intraperitoneal injection. NMN significantly increased the level of NAD+ in the heart at baseline and prevented a decrease in NAD+ during ischemia. NMN protected the heart from I/R injury when it was applied once 30 minutes before ischemia or 4 times just before and during reperfusion, suggesting that exogenous NMN protects the heart from I/R injury in both ischemic and reperfusion phases. The protective effect of NMN was accompanied by decreases in acetylation of FoxO1, but it was not obvious in Sirt1 KO mice, suggesting that the effect of NMN is mediated through activation of Sirt1. Compared to control diet (90% calories), CR (60% calories for 6 weeks) in mice led to a significant reduction in I/R injury, accompanied by upregulation of Nampt. The protective effect of CR against I/R injury was not significant in cardiac-specific Sirt1 KO mice, suggesting that the protective effect of CR is in part mediated through the Nampt-Sirt1 pathway. In conclusion, exogenous application of NMN and CR protects the heart by both mimicking IPC and activating Sirt1.

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The cardioprotective effect of NMN depends on Sirt1 expression.A, Acetylation levels of FoxO1 after 30 minutes of ischemia or sham operation with or without NMN administration. n = 4. n.s., not significant; # p<0.05, ## p<0.01 vs. respective sham-operated group. B and C, Either NMN (500 mg/kg) or vehicle (PBS) was administered (i.p. injection) to control or cardiac-specific Sirt1 knockout (Sirt1KO) mice 30 minutes before subjecting the mice to 30 minutes of ischemia followed by 24 hours of reperfusion (I/R). The extent of infarction was evaluated with TTC staining. Infarct area/AAR (B) and AAR (C) are shown. n = 4 to 5. n.s., not significant; * p<0.05, ## p<0.01 vs. respective control mice group. D, Schematic model of the protective effect of NMN against I/R injury. IPC: ischemic preconditioning; CR: caloric restriction; NMN: nicotinamide mononucleotide; NAD: nicotinamide adenine dinucleotide; I/R: ischemia/reperfusion.
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pone-0098972-g005: The cardioprotective effect of NMN depends on Sirt1 expression.A, Acetylation levels of FoxO1 after 30 minutes of ischemia or sham operation with or without NMN administration. n = 4. n.s., not significant; # p<0.05, ## p<0.01 vs. respective sham-operated group. B and C, Either NMN (500 mg/kg) or vehicle (PBS) was administered (i.p. injection) to control or cardiac-specific Sirt1 knockout (Sirt1KO) mice 30 minutes before subjecting the mice to 30 minutes of ischemia followed by 24 hours of reperfusion (I/R). The extent of infarction was evaluated with TTC staining. Infarct area/AAR (B) and AAR (C) are shown. n = 4 to 5. n.s., not significant; * p<0.05, ## p<0.01 vs. respective control mice group. D, Schematic model of the protective effect of NMN against I/R injury. IPC: ischemic preconditioning; CR: caloric restriction; NMN: nicotinamide mononucleotide; NAD: nicotinamide adenine dinucleotide; I/R: ischemia/reperfusion.

Mentions: NAD+ is a coenzyme of multiple enzymatic reactions. Given that Sirt1, an NAD+-dependent protein deacetylase, protects the heart from I/R injury [8], the protective effect of NMN against I/R may be mediated through activation of Sirt1. Myocardial ischemia significantly increased acetylation of FoxO1, a major target of Sirt1, whereas NMN significantly attenuated ischemia-induced increases in FoxO1 acetylation (Figure 5A). Based on these results, we hypothesized that the deacetylation activity of Sirt1 may contribute to the protective effect of NMN against I/R. To test this hypothesis, cardiac-specific Sirt1 knockout (Sirt1 c-KO) and control mice were subjected to I/R with or without NMN administration 30 min before ischemia (Figure 5B and 5C). In the control mice, the infarct was significantly smaller in the NMN-administered group than in the vehicle-treated group (AAR: NMN = 30±1.7%, vehicle = 31±1.1%, n.s.; IA/AAR: NMN = 24±1.9%, vehicle = 33±2.5%, p<0.05, n = 5). The infarct was significantly larger in vehicle-administered Sirt1c-KO mice than in vehicle-administered control mice (AAR: Sirt1 c-KO = 29±1.9%, control = 31±1.1%, n.s.; IA/AAR: Sirt1 c-KO  = 51±2.9%, control = 33±2.5%, p<0.01, n = 5). Furthermore, NMN administration failed to reduce the infarct size in Sirt1c-KO mice (AAR: NMN = 29±1.5%, vehicle = 29±1.9%, n.s.; IA/AAR: NMN = 51±2.9%, vehicle = 51±3.4%, n.s., n = 4 to 5). This suggests that the protective effect of NMN against I/R injury is in part mediated through Sirt1, an NAD+-dependent enzyme (Figure 5D).


Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion.

Yamamoto T, Byun J, Zhai P, Ikeda Y, Oka S, Sadoshima J - PLoS ONE (2014)

The cardioprotective effect of NMN depends on Sirt1 expression.A, Acetylation levels of FoxO1 after 30 minutes of ischemia or sham operation with or without NMN administration. n = 4. n.s., not significant; # p<0.05, ## p<0.01 vs. respective sham-operated group. B and C, Either NMN (500 mg/kg) or vehicle (PBS) was administered (i.p. injection) to control or cardiac-specific Sirt1 knockout (Sirt1KO) mice 30 minutes before subjecting the mice to 30 minutes of ischemia followed by 24 hours of reperfusion (I/R). The extent of infarction was evaluated with TTC staining. Infarct area/AAR (B) and AAR (C) are shown. n = 4 to 5. n.s., not significant; * p<0.05, ## p<0.01 vs. respective control mice group. D, Schematic model of the protective effect of NMN against I/R injury. IPC: ischemic preconditioning; CR: caloric restriction; NMN: nicotinamide mononucleotide; NAD: nicotinamide adenine dinucleotide; I/R: ischemia/reperfusion.
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pone-0098972-g005: The cardioprotective effect of NMN depends on Sirt1 expression.A, Acetylation levels of FoxO1 after 30 minutes of ischemia or sham operation with or without NMN administration. n = 4. n.s., not significant; # p<0.05, ## p<0.01 vs. respective sham-operated group. B and C, Either NMN (500 mg/kg) or vehicle (PBS) was administered (i.p. injection) to control or cardiac-specific Sirt1 knockout (Sirt1KO) mice 30 minutes before subjecting the mice to 30 minutes of ischemia followed by 24 hours of reperfusion (I/R). The extent of infarction was evaluated with TTC staining. Infarct area/AAR (B) and AAR (C) are shown. n = 4 to 5. n.s., not significant; * p<0.05, ## p<0.01 vs. respective control mice group. D, Schematic model of the protective effect of NMN against I/R injury. IPC: ischemic preconditioning; CR: caloric restriction; NMN: nicotinamide mononucleotide; NAD: nicotinamide adenine dinucleotide; I/R: ischemia/reperfusion.
Mentions: NAD+ is a coenzyme of multiple enzymatic reactions. Given that Sirt1, an NAD+-dependent protein deacetylase, protects the heart from I/R injury [8], the protective effect of NMN against I/R may be mediated through activation of Sirt1. Myocardial ischemia significantly increased acetylation of FoxO1, a major target of Sirt1, whereas NMN significantly attenuated ischemia-induced increases in FoxO1 acetylation (Figure 5A). Based on these results, we hypothesized that the deacetylation activity of Sirt1 may contribute to the protective effect of NMN against I/R. To test this hypothesis, cardiac-specific Sirt1 knockout (Sirt1 c-KO) and control mice were subjected to I/R with or without NMN administration 30 min before ischemia (Figure 5B and 5C). In the control mice, the infarct was significantly smaller in the NMN-administered group than in the vehicle-treated group (AAR: NMN = 30±1.7%, vehicle = 31±1.1%, n.s.; IA/AAR: NMN = 24±1.9%, vehicle = 33±2.5%, p<0.05, n = 5). The infarct was significantly larger in vehicle-administered Sirt1c-KO mice than in vehicle-administered control mice (AAR: Sirt1 c-KO = 29±1.9%, control = 31±1.1%, n.s.; IA/AAR: Sirt1 c-KO  = 51±2.9%, control = 33±2.5%, p<0.01, n = 5). Furthermore, NMN administration failed to reduce the infarct size in Sirt1c-KO mice (AAR: NMN = 29±1.5%, vehicle = 29±1.9%, n.s.; IA/AAR: NMN = 51±2.9%, vehicle = 51±3.4%, n.s., n = 4 to 5). This suggests that the protective effect of NMN against I/R injury is in part mediated through Sirt1, an NAD+-dependent enzyme (Figure 5D).

Bottom Line: The protective effect of NMN was accompanied by decreases in acetylation of FoxO1, but it was not obvious in Sirt1 KO mice, suggesting that the effect of NMN is mediated through activation of Sirt1.The protective effect of CR against I/R injury was not significant in cardiac-specific Sirt1 KO mice, suggesting that the protective effect of CR is in part mediated through the Nampt-Sirt1 pathway.In conclusion, exogenous application of NMN and CR protects the heart by both mimicking IPC and activating Sirt1.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, New Jersey, United States of America.

ABSTRACT
Nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme for nicotinamide adenine dinucleotide (NAD+) synthesis, and Sirt1, an NAD+-dependent histone deacetylase, protect the heart against ischemia/reperfusion (I/R). It remains unknown whether Nampt mediates the protective effect of ischemic preconditioning (IPC), whether nicotinamide mononucleotide (NMN, 500 mg/kg), a product of Nampt in the NAD+ salvage pathway, mimics the effect of IPC, or whether caloric restriction (CR) upregulates Nampt and protects the heart through a Sirt1-dependent mechanism. IPC upregulated Nampt protein, and the protective effect of IPC against ischemia (30 minutes) and reperfusion (24 hours) was attenuated at both early and late phases in Nampt +/- mice, suggesting that Nampt plays an essential role in mediating the protective effect of IPC. In order to mimic the effect of Nampt, NMN was administered by intraperitoneal injection. NMN significantly increased the level of NAD+ in the heart at baseline and prevented a decrease in NAD+ during ischemia. NMN protected the heart from I/R injury when it was applied once 30 minutes before ischemia or 4 times just before and during reperfusion, suggesting that exogenous NMN protects the heart from I/R injury in both ischemic and reperfusion phases. The protective effect of NMN was accompanied by decreases in acetylation of FoxO1, but it was not obvious in Sirt1 KO mice, suggesting that the effect of NMN is mediated through activation of Sirt1. Compared to control diet (90% calories), CR (60% calories for 6 weeks) in mice led to a significant reduction in I/R injury, accompanied by upregulation of Nampt. The protective effect of CR against I/R injury was not significant in cardiac-specific Sirt1 KO mice, suggesting that the protective effect of CR is in part mediated through the Nampt-Sirt1 pathway. In conclusion, exogenous application of NMN and CR protects the heart by both mimicking IPC and activating Sirt1.

Show MeSH
Related in: MedlinePlus